The modulation of cell-mediated immune responses (including T- and antibody-mediated immune responses) is important in a therapeutic context.
Organ and cell transplantation is the treatment of choice for most patients with end stage kidney-failure, heart or liver disease, autoimmune type 1 diabetes and it is a developing possibility for patients with deficiencies in small-bowel function. Graft survival depends on a number of factors but the most significant of these is the administration of powerful immunosuppressive drugs. Transplantation between genetically disparate individuals evokes a rapid and potentially destructive alloreactive immune response that, if left uncontrolled, can lead to complete destruction of the transplanted organ or to graft versus host disease (GVHD). Administration of immunosuppressive drugs attenuates this response and thus prevents acute graft rejection. However, continued graft survival depends on life-long or prolonged immunosuppression because withdrawal of immunosuppression results in re-activation of the rejection response, leading to rapid graft destruction.
Although the currently available immunosuppressive drugs are very effective in short term, substantial problems indicate a pressing need to develop alternative and more sophisticated ways of preventing graft rejection. The main obstacle is the inability to distinguish between beneficial immune responses against infectious pathogens and destructive immune responses against the graft. Thus, immunosuppressive therapies can lead to increased risk of opportunistic infections. Several studies show that non-specific immunosuppression would lead to an increased incidence of cancer in transplanted patients (Hojo 1999). Therefore, the full potential of transplantation will be realised only when alternatives to non-specific immunosuppression will be found. The major aim of transplantation immunology is to develop protocols that prevent immune responses towards the graft but leave the rest of the immune system intact. This accomplishment will lead to transplantation tolerance.
In autoimmune diseases, undesired immune responses to self-antigens lead to destruction of peripheral tissues. Treatments of autoimmune diseases are currently based on down-modulation of inflammation and non-antigen (Ag) specific immunosuppression. As for prevention of allograft rejection, this strategy is frequently not effective in the long term with high risk of relapse once the drug is withdrawn and hazards of excessive immunosuppression, including infections and tumors. The alternative approach is based on the induction of transient immunosuppression and/or specific immune tolerance, aimed at “silencing” the pathogenic response to self-Ag, while keeping host defense mechanisms intact.
The immune system has evolved two distinct mechanisms to induce tolerance to self or non-harmful antigens. These are referred to as central and peripheral T cell tolerance. Central tolerance is realized during fetal development and the very early natal period and is mediated by clonal deletion of self-reactive T cells during thymic development. Peripheral mechanisms induce tolerance in mature T cells and occur in the periphery during the whole life. These mechanisms include functional inactivation of antigen specific lymphocytes (named anergy) and activation of T cell subsets with suppressive and regulatory capacities (reviewed in Battaglia 2002).
Recently, there has been a growing interest in the induction of T regulatory (Tr) cells as a strategy to achieve immunological tolerance. The majority of Tr cells identified to date lie within the CD4+ population, and the CD4+ Tr cells that constitutively express the IL-2Rα chain (CD25) are one of the best characterized so far both in mouse and humans. Our invention concentrates on this Tr cell subset identified as CD4+CD25+ Tr cells.